This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 2 diabetes is characterized by insulin resistance, impaired insulin secretion, and hyperglycemia. Oklahoma American Indians have an age-adjusted diabetes prevalence three times that of whites, and a diabetes-related death rate 1.8 times that of whites. Both genetic and environmental factors are suggested to underlie this disparity. This project investigates the genetic factors, environmental factors, and genotype by environment interaction effects influencing 14 diabetes-related phenotypes in Oklahoma American Indians: fasting and 2-hour plasma glucose concentrations;fasting and 2-hour serum insulin concentrations; serum triglyceride level;HDL cholesterol concentration;systolic and diastolic blood pressure;age of diabetes onset;body mass index;waist-to-hip ratio;and levels of fibrinogen, PAI-1, and C-reactive protein. Phenotype data will be collected from medical records of 184 adult, affected sib pairs. Age, sex, ancestry, diet, activity, and other environmental data will be taken from medical records and questionnaires. Sib pairs and their first degree relatives (used to establish allelic identity by state) will be genotyped for 6000 single nucleotide polymorphisms (SNPs). The objective is to use variance components-based statistical genetics methods to localize genetic factors that contribute to phenotype variation, and to investigate the extent to which genetic effects vary by environment. The specific aims are to: 1) use quantitative genetics methods to estimate the contribution of additive genetic and measured environmental covariates to variation in 14 diabetes-related phenotypes in American Indian sib pairs;2) use quantitative genetics methods to examine genotype-by-environment interaction effects influencing the phenotypes;and 3) use genome-wide multipoint linkage analyses to detect evidence of phenotype linkage to chromosomal regions represented by highly informative autosomal SNP markers. The long-term goal is to identify genetic and environmental factors of potential use in developing culturally appropriate interventions and treatments. Relevance: The high prevalence of type 2 diabetes in American Indian communities in Oklahoma constitutes a major public health crisis. The identification of genetic and environmental components of diabetes risk is necessary to the development of effective, culturally-appropriate intervention and treatment strategies.